An overwhelming majority of the world's population will experience some degree of vision loss in their lifetime. Vision loss affects virtually all people regardless of age, race, economic or social status, or geographical location. Ocular-related disorders, while often not life threatening, necessitate life-style changes that jeopardize the independence of the afflicted individual. Vision impairment can result from most all ocular disorders, including diabetic retinopathies, proliferative retinopathies, retinal detachment, toxic retinopathies, retinal vascular diseases, retinal degenerations, vascular anomalies, age-related macular degeneration and other acquired disorders, infectious diseases, inflammatory diseases, ocular ischemia, pregnancy-related disorders, retinal tumors, choroidal tumors, choroidal disorders, vitreous disorders, trauma, cataract complications, dry eye, and inflammatory optic neuropathies.
Leading causes of severe vision loss and blindness are ocular-related disorders wherein the vasculature of the eye is damaged or insufficiently regulated. Ocular-related diseases comprising a neovascularization complication are many and include, for example, exudative age-related macular degeneration, diabetic retinopathy, corneal neovascularization, choroidal neovascularization, cyclitis, Hippel-Lindau Disease, retinopathy of prematurity, pterygium, histoplasmosis, iris neovascularization, macular edema, glaucoma-associated neovascularization, and the like. It is likely that severe vision loss does not result directly from neovascularization, but the effect of neovascularization on the retina. The retina is a delicate ocular membrane on which images are received. Near the center of the retina is the macula lutea, an oval area of retinal tissue where visual sense is most acute. The retina is most delicate at the fovea centralis, the central depression located in the center of the macula. Damage of the retina, i.e., retinal detachment, retinal tears, or retinal degeneration, is directly connected to vision loss. A common cause of retinal detachment, retinal tears, and retinal degeneration is abnormal, i.e., uncontrolled, vascularization of various ocular tissues, although a small percentage of cases are due to atrophic complications. Disorders associated with both neovascular and atrophic components, such as age-related macular degeneration and diabetic retinopathy, are particularly difficult to treat due to the emergence of a wide variety of complications.
Age-related macular degeneration (AMD) is the leading cause of blindness in patients over 65 years of age. As the elderly population of the world increases, the incidence of age-related macular degeneration is expected to increase dramatically, reaching a predicted 7.5 million cases in the United States alone by the year 2030 (Hyman et al., Am. J. Epidemiol., 118, 213-227 (1983)). Age-related macular degeneration is a progressive, degenerative disorder of the eye resulting initially in loss of visual acuity. Many patients afflicted with AMD experience exudative complications, including disciform scars (i.e., scarring involving fibrous elements) and neovascularization. Severe vision loss occurs as neovascularization or atrophy disturbs the foveal center (Bressler et al., Opthalmology, 102, 1206-1211 (1995)). Ultimately, legal blindness from age-related macular degeneration stems from degeneration of the RPE and the subsequent death of photoreceptors.
Like AMD, diabetic retinopathy is subdivided into a nonproliferative stage, which typically occurs first, and a proliferative stage. The proliferative stage of diabetic retinopathy is characterized by neovascularization and fibrovascular growth (i.e., scarring involving glial and fibrous elements) from the retina or optic nerve over the inner surface of the retina or disc or into the vitreous cavity.
Abnormal vascularization of the eye also can occur in the layer directly underneath the retina, i.e., the choroid. Choroidal neovascularization (CNV) is often associated with AMD and results in leakage, bleeding, and scarring in the macula. Scarring in the macula results in a central scotoma (interruption of the visual field) and loss of reading and driving vision. Choroidal neovascularization is detected using angiography, e.g., fluorescein angiography, alone or in combination with indocyanine-green angiography.
For many ocular-related disorders, there are currently no effective therapeutic options. Laser photocoagulation, the administration of laser burns to various areas of the eye, is used in the treatment of many neovascularization-linked disorders. For example, focal macular photocoagulation is used to treat areas of vascular leakage in the macula (Murphy, Amer. Family Physician, 51(4), 785-796 (1995)). Similarly, neovascularization, in particular, advanced proliferative retinopathy, is commonly treated with scatter or panretinal photocoagulation. However, laser treatment may cause permanent blind spots corresponding to the treated areas. With respect to age-related macular degeneration, many patients eventually experience severe vision loss in spite of treatment. Other treatment options for ocular-related disorders include thermotherapy, photodynamic therapy, radiation therapy, and surgery to either translocate the macula or remove the abnormal blood vessels. However, only photodynamic therapy and focal laser have been found to be better than no treatment at all, and the treatment effect is marginal and temporary.
Given the prevalence of ocular-related disorders and the lack of effective treatments, there remains a need for an effective prophylactic and therapeutic treatment of ocular-related disorders, in particular ocular-related disorders with complications associated with abnormal cellular proliferation (e.g., neovascularization), such as diabetic retinopathy, age-related macular degeneration, and choroidal neovascularization. Accordingly, the invention provides materials and methods for prophylactically and therapeutically treating disorders associated with neovascularization, in particular, ocular-related disorders associated with neovascularization. This and other advantages of the invention will become apparent from the detailed description provided herein.